ABSTRACT: The AMP-AD Target Discovery and Preclinical Validation Project aims to reduce the time between the discovery of potential drug targets and the development of new drugs for Alzheimer?s disease (AD) treatment and prevention (RFA-AG-18-013). The six involved consortia under AMP-AD have generated large-scale molecular data from human brain samples with network modeling approaches and experimental validation that defined novel potential drug targets for AD. A major challenge for the next phase is to provide a deeper molecular understanding of key implicated pathways and their enzymes, transporters and signaling molecules that are amenable for drug discovery efforts. Defining a molecular basis for heterogeneity within disease is critical for successful drug development within a precision medicine context. Our AD Metabolomics Consortium (ADMC) became part of AMP-AD one-year post inception of Phase I, adding the power of metabolomics to these efforts. AD has foundational metabolic changes that happen early and pre-symptomatically. Most of the genes implicated in AD suggest a role for lipid processing, immune function regulation, and phagocytosis that are all related to metabolic functions. Detailed biochemical knowledge advanced the medical field, providing tools for monitoring disease, such as measures of glucose and cholesterol in diabetes and cardiovascular diseases, and resulted in development of drugs, such as statins and antidepressants. In Phase I, we helped to define biochemical trajectories of disease bridging peripheral and brain metabolic changes to AMP-AD. We built metabolic networks for early changes in AD that correlate with CSF and brain imaging changes, defining sex differences and their biochemical trajectories of disease, identifying the role of the gut microbiome and liver in cognitive decline and brain glucose changes and atrophy, supporting the importance of the gut-liver-brain axis in AD. In addition, we have highlighted two classes of drugs for possible repurposing (from MS and fatty liver disease) We have informed three other consortia within AMP-AD about their putative targets, supporting them with links to biochemical pathways and bringing seemingly diverse omics findings to common biochemical pathways. During AMP-AD Phase II, we propose to expand metabolomic analyses to accelerate AMP-AD progress towards novel drug discovery. By working with AMP-AD partners, we will systematically address contributions of peripheral metabolism to brain health and disease and will provide biochemical readouts as an intermediate phenotype for rich omics data generated in the consortium. By profiling and analyzing samples from large community studies pre-symptomatically and by building an Atlas connecting genotypes and metabolomic signatures of AD we hope to provide biochemical insights about mechanisms and sub-classes of disease. In summary, the ADMC will provide an enabling metabolic interconnecting framework to accelerated AD therapeutic developing in AMP-AD.